We propose to elucidate mechanisms of early development of the inner ear in the zebrafish, Danio rerio. The inner ear arises form a simple thickening on the surface of the embryo termed the otic placode, which subsequently forms the otic vesicle where sensory epithelia and neurons of the ear arise. We have shown that each of these processes requires Fgf signaling. At each step pax2/5/8 genes are induced by Fgf and help mediate or amplify Fgf signaling. In three specific aims we will examine how pax2/5/8 genes function and interact with other stage- and region-specific cofactors. 1) We will test specific functions of pax8 in otic placode induction and its interactions with coregulated genes sox3 and gbx2. 2) We will test a model in which Fgf stimulates ongoing formation of sensory epithelia by co-inducing pax2/5 genes, sox2 and proneural genes atoh1a and atoh1b (related to Math1). We hypothesize these genes regulate distinct aspects of specification, differentiation and survival of sensory hair cells. 3) We will test the role of Fgf and pax2/5 genes in regulating the expression and function of another proneural gene, neurog1, during formation of otic neuroblasts. Neuroblasts normally form in close proximity to sensory epithelia and we hypothesize that pax2/5 genes help distinguish the different responses to local Fgfs. To facilitate these aims, we will make use of heat shock- inducible transgenes to test the effects of misexpressing various genes at specific times and locations. Combined with loss-of-function approaches, these studies will provide fundamental insights into mechanisms of otic placode induction and sensory/neural development. These processes and regulatory functions are highly conserved. Moreover, studying the effects of misexpressing proneural genes in zebrafish could inform efforts to use similar approaches to restore hearing in mammals.

Public Health Relevance

Loss of hearing is a common affliction and results from permanent loss of sensory hair cells and/or neurons of the inner ear. It is widely believed that the key to restoring hearing in humans lies in reactivating the developmental processes by which hair cells and neurons first develop in the embryo. Using zebrafish as a model, we are investigating the functions of genes believed to regulate these processes in all vertebrates.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Auditory System Study Section (AUD)
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Freeman, Nancy
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Texas A&M University
Schools of Arts and Sciences
College Station
United States
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Gou, Yunzi; Vemaraju, Shruti; Sweet, Elly M et al. (2018) sox2 and sox3 Play unique roles in development of hair cells and neurons in the zebrafish inner ear. Dev Biol 435:73-83
Gou, Yunzi; Guo, Jinbai; Maulding, Kirstin et al. (2018) sox2 and sox3 cooperate to regulate otic/epibranchial placode induction in zebrafish. Dev Biol 435:84-95
Kantarci, Husniye; Gerberding, Andrea; Riley, Bruce B (2016) Spemann organizer gene Goosecoid promotes delamination of neuroblasts from the otic vesicle. Proc Natl Acad Sci U S A 113:E6840-E6848
Kantarci, Husniye; Edlund, Renee K; Groves, Andrew K et al. (2015) Tfap2a promotes specification and maturation of neurons in the inner ear through modulation of Bmp, Fgf and notch signaling. PLoS Genet 11:e1005037
Edlund, Renée K; Ohyama, Takahiro; Kantarci, Husniye et al. (2014) Foxi transcription factors promote pharyngeal arch development by regulating formation of FGF signaling centers. Dev Biol 390:1-13
Maulding, Kirstin; Padanad, Mahesh S; Dong, Jennifer et al. (2014) Mesodermal Fgf10b cooperates with other fibroblast growth factors during induction of otic and epibranchial placodes in zebrafish. Dev Dyn 243:1275-85
Bhat, Neha; Kwon, Hye-Joo; Riley, Bruce B (2013) A gene network that coordinates preplacodal competence and neural crest specification in zebrafish. Dev Biol 373:107-17
Vemaraju, Shruti; Kantarci, Husniye; Padanad, Mahesh S et al. (2012) A spatial and temporal gradient of Fgf differentially regulates distinct stages of neural development in the zebrafish inner ear. PLoS Genet 8:e1003068
Padanad, Mahesh S; Bhat, Neha; Guo, Biwei et al. (2012) Conditions that influence the response to Fgf during otic placode induction. Dev Biol 364:1-10
Sweet, Elly M; Vemaraju, Shruti; Riley, Bruce B (2011) Sox2 and Fgf interact with Atoh1 to promote sensory competence throughout the zebrafish inner ear. Dev Biol 358:113-21

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